The approach taken was to select for the outgrowth of Fas-resistant/refractory (FasR) CMS4 cells by in vitro serial co-culture with agonistic anti-Fas stimuli (as a surrogate trigger for Fas engagement) and then compare the selected with the unselected tumor cells for differences in metastatic behavior. Overall, FasR CMS4 tumor cells were produced, which exhibited enhanced lung metastatic ability. However, simply disrupting the Fas pathway molecularly in the parental tumor failed to achieve the same metastatic outcome. This suggested that a metastatic-competent phenotype likely consisted of Fas-resistant neoplastic subpopulations that also coexpressed additional intrinsic malignant characteristics. Similarly, we extended these observations to a human primary and metastatic colon carcinoma cell model. We found that metastatic subpopulations could be selectively enriched by functional depletion of Fas-responsive cells within the heterogeneous primary tumor. Taken collectively, these data revealed a previously unrecognized contribution of the Fas pathway in tumor progression, and suggested that Fas-based interactions impose an immunologic or biologic selective pressure favoring the emergence of such pre-existent malignant/metastatic subpopulations. Lastly, the gene expression patterns between the human primary colon carcinoma cell line and its metastatic counterpart were compared, which led to the identification of a number of genes that were strongly differentially expressed. Two key signaling defects in these tumor cells were identified that accounted for, at least in part, resistance to Fas-mediated death---one was involved in IFN-gamma-mediated signaling, interferon consensus sequence binding protein (ICSBP), and the other involved in Fas-mediated signaling, caspase-1. These findings support the hypothesis that an alteration in these signaling events may contribute to a more apoptotic-resistant phenotype, which, in turn, may influence malignant/metastatic potential.